Accounting for local incidence when estimating rotavirus vaccine efficacy among countries: a pooled analysis of monovalent rotavirus vaccine trials

Abstract

Rotavirus vaccine appears to perform sub-optimally in countries with higher rotavirus burden. We hypothesized that differences in the magnitude of rotavirus exposures may bias vaccine efficacy (VE) estimates, so true differences in country-specific rotavirus VE would be exaggerated without accommodating differences in exposure. We estimated VE against any-severity and severe rotavirus gastroenteritis (RVGE) using Poisson regression models fit to pooled individual-level data from Phase II and III monovalent rotavirus vaccine trials conducted between 2000 and 2012. The standard approach model included terms for vaccination, country, and a vaccination-country interaction. Other models used proxies for exposure magnitude like severe RVGE rate or age at severe RVGE instead of country. Country-specific proxies were calculated from placebo group data or extracted from an external meta-analysis. Analyses included 83,592 infants from 23 countries in the Americas, Europe, Africa, and Asia. Using the standard approach, VE against severe RVGE substantially varied (10-100%). Using the severe RVGE rate proxy brought VE from all but two countries between 80% and 86%. Heterogeneity for VE against any-severity RVGE was similarly attenuated. Adjusting for exposure proxies reduced heterogeneity in country-specific rotavirus VE estimates. This phenomenon may extend to other vaccines against partially immunizing pathogens with global disparities in burden.

Keywords: bias; clinical trials; force of infection; infectious exposures; rotavirus; vaccine efficacy.